How Well Do We Know the Future of CO2 Emissions? Projecting Fleet Emissions from Light Duty Vehicle Technology Drivers.

While the UK has committed to reduce CO2 emissions to 80% of 1990 levels by 2050, transport accounts for nearly a fourth of all emissions and the degree to which decarbonization can occur is highly uncertain. We present a new methodology using vehicle and powertrain parameters within a Bayesian framework to determine the impact of engineering vehicle improvements on fuel consumption and CO2 emissions. Our results show how design changes in vehicle parameters (e.g., mass, engine size, and compression ratio) result in fuel consumption improvements from a fleet-wide mean of 5.6 L/100 km in 2014 to 3.0 L/100 km by 2030. The change in vehicle efficiency coupled with increases in vehicle numbers and fleet-wide activity result in a total fleet-wide reduction of 41 ± 10% in 2030, relative to 2012. Concerted internal combustion engine improvements result in a 48 ± 10% reduction of CO2 emissions, while efforts to increase the number of diesel vehicles within the fleet had little additional effect. Increasing plug-in and all-electric vehicles reduced CO2 emissions by less (42 ± 10% reduction) than concerted internal combustion engines improvements. However, if the grid decarbonizes, electric vehicles reduce emissions by 45 ± 9% with further reduction potential to 2050.

Nasal reconstruction in panfacial burns: useful techniques in challenging cases.

Nasal reconstruction after severe panfacial burns can be challenging to correct because of scarring, loss of suitable donor sites, and variably limited blood supply of local flaps. We describe 2 cases of subtotal nasal reconstruction in which we overcame these difficulties. Both cases had alar subunit loss, which had left significant functional and esthetic deformities. However, both cases were managed very differently because of availability of donor sites.The first patient had 70% total body surface area burns with bilateral alar subunit loss: nasal reconstruction required a meticulous multistaged forehead flap. The second patient required nasal reconstruction using a turn-down flap to maximize take of a composite graft from previously burned ear donor sites.A number of surgical techniques have been described to manage subtotal burns nasal reconstruction, foremost of which are the nasolabial and paramedian forehead flaps. Cartilage grafts from the septum and the conchal bowl can be integrated into these flaps. Composite grafts can be unpredictable and are often used with caution.Such cases demonstrate that large composite grafts can be an extremely robust method of reconstruction even in a subset of patients with extensively scarred recipient and donor sites. In our second case, composite grafting avoided multistaged procedures such as the forehead flap and can be considered as a first-line procedure in large alar subunit loss.

Cumulative sum (CUSUM) analysis: A 10 year experience of outcome monitoring in a regional burn centre.

INTRODUCTION: Outcome monitoring can identify fluctuations in healthcare. Cumulative sum (CUSUM) analysis can detect when mortality deviates from expected, allowing early intervention through targeted audit. We present a 10-year experience of the prospective use of CUSUM methodology in a regional burn centre. METHOD: Prospective outcome monitoring was conducted for all admissions to the intensive care unit between 2012 and 2022. The revised Baux score was used for mortality risk prediction. Risk-adjusted CUSUM charts tracked mortality against that predicted by the revised Baux score. Deviations from expected outcomes triggered detailed structured analysis. Learning outcomes were identified from internal and external governance groups. RESULTS: CUSUM analysis was triggered on eight occasions: one paediatric (excess deaths), six adult (four excess survivors, two excess deaths) and one elderly (excess survivors). Detailed analysis identified areas for continuous improvement and positive themes from excess survivors. CONCLUSION: The use of CUSUM as an early warning trigger stimulates assessment of practice and critical appraisal of factors contributing to unexpected mortality or survival. The revised Baux score at its foundation needs to be carefully considered but remains a valid model. One benefit is positive reinforcement of team cohesion and morale during periods of care excellence leading to excess survivors.

Recovery of functional independence following major burn: A systematic review.

BACKGROUND: Major burn injury, despite advancements in care and prevention, can have a profound impact on long-term morbidity, affecting quality of life and socioeconomic standing. We aim to explore factors predicting recovery of independence, the expected rate and time in majorly burned patients, and the measures of progress used. METHOD: A systematic search of four databases (MEDLINE, EMBASE, COCHRANE, CINAHL) was conducted for studies reporting outcomes pertaining to physical ability indicative of independent function in adult (>15 y) cohorts who had suffered a major burn (>20% TBSA) up to 30 years after treatment in a developed specialised burn service. Data extracted included factors affecting rate of and time to achievement of function in five independence domains, as well as the outcome measures used. RESULTS: 21 eligible studies were included comprising 1298 major burns survivors with a combined mean age of 39.6 y and a mean TBSA of 25.8%. The most significant recurring factors impacting recovery of independent function were older age, female gender, burn severity, prolonged ICU and hospital admission, preceding mental health conditions, and post-acute psychological issues. Exercise-based rehabilitation conferred benefits on major burn patients even over 2 years following injury. Discharge to independent living from hospital occurred in 27% to 97% of patients, while reported return to work rates varied from 52% to 80%. Burns Specific Health Scale-Brief, Functional Independence Measure, and Physical Composite Score (SF-36) were the most widely used outcome scoring systems. CONCLUSION: Major burn survivors have protracted recovery with potential for persistent chronic impairments, remaining consistently below baseline levels of function. Non-modifiable factors such as age and gender, and disease characteristics such as burn size with associated physical, physiological and psychosocial sequelae are contributory. Further research is required to explore achievement of specific milestones of major burn and polytrauma critical care patients, while early targeted rehabilitation addressing physical, psychological, and vocational needs has promising potential benefit.

An eighteen-year review of intensive care requirements for paediatric burns in a regional burns service.

INTRODUCTION: Advances in burns management have reduced mortality. Consequently, efficient resource management plays an increasingly important role in improving paediatric burns care. This study aims to assess the support requirements and outcomes of paediatric burns patients admitted to a burns centre intensive care unit in comparison to established benchmarks in burns care. METHOD: A retrospective review of burns patients under the age of 16 years old, admitted to a regional burns service intensive care unit between March 1998 and March 2016 was conducted. RESULTS: Our analysis included 234 patients, with the percentage of TBSA affected by burn injury ranging from 1.5% to 95.0%. The median (IQR) %TBSA was 20.0% (11.0-30.0), and the observed mortality rate was 2.6% (6/234). The median (IQR) length of stay was 0.7 days/%TBSA burn (0.4-1.2), 17.9% (41/229) required circulatory support and 2.6% (6/234) required renal replacement. Mortality correlated with smoke inhalation injury (P < 0.001), %TBSA burn (P = 0.049) and complications (P = 0.004) including infections (P = 0.013). CONCLUSIONS: Among children with burn injuries who require intensive care, the presence of inhalational injury and the diagnosis of infection are positively correlated with mortality. Understanding the requirements for organ support can facilitate a more effective allocation of resources within a burns service.

Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014.

The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC(50), led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).

Aldehyde Dehydrogenase, a Marker of Normal and Malignant Stem Cells, Typifies Mesenchymal Progenitors in Perivascular Niches.

Innate mesenchymal stem cells exhibiting multilineage differentiation and tissue (re)generative-or pathogenic-properties reside in perivascular niches. Subsets of these progenitors are committed to either osteo-, adipo-, or fibrogenesis, suggesting the existence of a developmental organization in blood vessel walls. We evaluated herein the activity of aldehyde dehydrogenase, a family of enzymes catalyzing the oxidation of aldehydes into carboxylic acids and a reported biomarker of normal and malignant stem cells, within human adipose tissue perivascular areas. A progression of ALDHLow to ALDHHigh CD34+ cells was identified in the tunica adventitia. Mesenchymal stem cell potential was confined to ALDHHigh cells, as assessed by proliferation and multilineage differentiation in vitro of cells sorted by flow cytometry with a fluorescent ALDH substrate. RNA sequencing confirmed and validated that ALDHHigh cells have a progenitor cell phenotype and provided evidence that the main isoform in this fraction is ALDH1A1, which was confirmed by immunohistochemistry. This demonstrates that ALDH activity, which marks hematopoietic progenitors and stem cells in diverse malignant tumors, also typifies native, blood vessel resident mesenchymal stem cells.

Early tracheostomy and active exercise programmes in adult intensive care patients with severe burns.

BACKGROUND: Tracheostomy is a strategy often employed in patients requiring prolonged intubation in ICU settings. Evidence suggests that earlier tracheostomy and early active exercise are associated with better patient centered outcomes. Severe burn patients often require prolonged ventilatory support due to their critical condition, complex sedation management and multiple operating room visits. It is still unclear the optimal timing for tracheostomy in this population. METHODS: We conducted a service evaluation where we compared Early Tracheostomy (≤10 days) with Late Tracheostomy (>10 days) in 41 severely burned patients that required prolonged respiratory support. RESULTS: Early Tracheostomy cohort was associated with fewer days of mechanical ventilation (16 vs 33, p = 0.001), shorter hospital length of stay (65 vs 88 days, p = 0.018), earlier first day of active exercise (day 8 vs day 25, p < 0.0001) and higher Functional Assessment for Burns scores upon discharge (32 vs 28, p = 0.016). CONCLUSION: Early tracheostomy in patients with severe burns is associated with earlier active exercise, fewer days of ventilation, shorter length of hospital stay and better physical functional independence upon discharge from hospital.

Synthesis of 4-alkyl-, 4-aryl- and 4-arylamino-5-aminoisoquinolin-1-ones and identification of a new PARP-2 selective inhibitor.

The considerable interest in substituted isoquinolin-1-ones related to 5-aminoisoquinolin-1-one (5-AIQ) as drugs points to a need for an efficient and straightforward synthesis of the 4,5-disubstituted bicycles. Bromination of 5-nitroisoquinolin-1-one gave 4-bromo-5-nitroisoquinolin-1-one but neither this nor 5-amino-4-bromoisoquinolin-1-one would participate in Pd-catalysed couplings. Protection of the lactam as 1-methoxy- and 1-benzyloxy-4-bromo-5-nitroisoquinolines, however, permitted Stille, Suzuki and Buchwald-Hartwig couplings to take place in high yields, insensitive to electronic demands and severe steric bulk in the arylboronic acids. Lithiation of 4-bromo-1-methoxy-5-nitroisoquinoline and quench with iodomethane gave 1-methoxy-4-methyl-5-nitroisoquinoline in low yield. Demethylation of the 1-methoxy-4-substituted-5-nitroisoquinolines with hydrogen bromide gave 4-substituted-5-nitroisoquinolin-1-ones, whereas hydrogenolytic debenzylation was achieved with simultaneous reduction of the 5-nitro group. 5-Amino-4-(4-trifluoromethylphenyl)isoquinolin-1-one was identified as a new potent and selective inhibitor of poly(ADP-ribose)polymerase-2 (PARP-2).

Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.

BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.

High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.

Whereas target-specific drugs are available for treating ERBB2-overexpressing and hormone receptor-positive breast cancers, no tailored therapy exists for hormone receptor- and ERBB2-negative ("triple-negative") mammary carcinomas. Triple-negative tumors account for 15% of all breast cancers and frequently harbor defects in DNA double-strand break repair through homologous recombination (HR), such as BRCA1 dysfunction. The DNA-repair defects characteristic of BRCA1-deficient cells confer sensitivity to poly(ADP-ribose) polymerase 1 (PARP1) inhibition, which could be relevant to treatment of triple-negative tumors. To evaluate PARP1 inhibition in a realistic in vivo setting, we tested the PARP inhibitor AZD2281 in a genetically engineered mouse model (GEMM) for BRCA1-associated breast cancer. Treatment of tumor-bearing mice with AZD2281 inhibited tumor growth without signs of toxicity, resulting in strongly increased survival. Long-term treatment with AZD2281 in this model did result in the development of drug resistance, caused by up-regulation of Abcb1a/b genes encoding P-glycoprotein efflux pumps. This resistance to AZD2281 could be reversed by coadministration of the P-glycoprotein inhibitor tariquidar. Combination of AZD2281 with cisplatin or carboplatin increased the recurrence-free and overall survival, suggesting that AZD2281 potentiates the effect of these DNA-damaging agents. Our results demonstrate in vivo efficacy of AZD2281 against BRCA1-deficient breast cancer and illustrate how GEMMs of cancer can be used for preclinical evaluation of novel therapeutics and for testing ways to overcome or circumvent therapy resistance.

Abdominal compartment syndrome in burns patients: Introduction of an evidence-based management guideline and algorithm.

ABSTRACT: Abdominal compartment syndrome is a serious potential complication of burn injury, and carries high morbidity and mortality. Although there are generalised published guidelines on managing the condition, to date no management algorithm has yet been published tailored specifically to the burn injury patient. We set out to examine the literature on the subject in order to produce an evidence based management guideline, with the aim of improving outcomes for these patients. The guideline covers early detection and assessment of the condition as well as optimum medical, surgical and postoperative management. We believe that this guideline provides a much needed benchmark for managing burns patients with raised intra-abdominal pressure, as well as providing a template for further research and improvements in care.

Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.

To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.

WITHDRAWN: Burns first aid practices amongst paediatric caregivers following secondary advice.

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The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase.

We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.

Identification and optimisation of novel and selective small molecular weight kinase inhibitors of mTOR.

A pharmacophore mapping approach, derived from previous experience of PIKK family enzymes, was used to identify a hit series of selective inhibitors of the mammalian target of rapamycin (mTOR). Subsequent refinement of the SAR around this hit series based on a tri-substituted triazine scaffold has led to the discovery of potent and selective inhibitors of mTOR.

Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin.

PURPOSE: To assess efficacy of the novel, selective poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor AZD2281 against newly established BRCA2-deficient mouse mammary tumor cell lines and to determine potential synergy between AZD2281 and cisplatin. EXPERIMENTAL DESIGN: We established and thoroughly characterized a panel of clonal cell lines from independent BRCA2-deficient mouse mammary tumors and BRCA2-proficient control tumors. Subsequently, we assessed sensitivity of these lines to conventional cytotoxic drugs and the novel PARP inhibitor AZD2281. Finally, in vitro combination studies were done to investigate interaction between AZD2281 and cisplatin. RESULTS: Genetic, transcriptional, and functional analyses confirmed the successful isolation of BRCA2-deficient and BRCA2-proficient mouse mammary tumor cell lines. Treatment of these cell lines with 11 different anticancer drugs or with gamma-irradiation showed that AZD2281, a novel and specific PARP inhibitor, caused the strongest differential growth inhibition of BRCA2-deficient versus BRCA2-proficient mammary tumor cells. Finally, drug combination studies showed synergistic cytotoxicity of AZD2281 and cisplatin against BRCA2-deficient cells but not against BRCA2-proficient control cells. CONCLUSION: We have successfully established the first set of BRCA2-deficient mammary tumor cell lines, which form an important addition to the existing preclinical models for BRCA-mutated breast cancer. The exquisite sensitivity of these cells to the PARP inhibitor AZD2281, alone or in combination with cisplatin, provides strong support for AZD2281 as a novel targeted therapeutic against BRCA-deficient cancers.